A correlation between opiate abuse and HIV/AIDS is important to study because opiates are known to cause immunosuppression, and opiate users constitute a major cohort among HIV-positive individuals. We have recently shown that morphine abuse increases virus replication in blood and cerebral compartment of SIV/SHIV-infected Indian rhesus macaques and accelerate onset of clinical disease. Furthermore, we have found that morphine-dependent macaques showed inverse correlation between virus evolution and disease progression. We have also shown that half of the animals, who died within 20 weeks post- infection, did not develop detectable virus-specific immune responses. Therefore our results along with few other recent reports support the phenomenon of opiate-mediated immunosuppression. In view of the fact that opiate abusers represent >25% of total HIV-positive individuals and that opiate abuse causes immunosuppression, it is expected that these individuals would develop weaker immune response when immunized with any vaccine (or candidate vaccine), and thereby vaccine would confer inferior protection against disease. This application is designed to address these issues. We will immunize morphine-dependent and control macaques with a clinically relevant DNA/MVA SHIV AIDS vaccine. These macaques will be monitored for the level and longevity of vaccine-induced cellular and humoral immune responses. The vaccine-mediated protection in these two groups would be monitored by challenge with a chimeric simian human immunodeficiency virus (SHIV89.6P). The results from this study will provide not only proof of concept studies, but also offer a clinically relevant information regarding fate of an AIDS vaccine in a high-risk (opiate-dependent) population. In view of lack of any information in any system makes this study more important because results obtained from this project will also provide an important guideline for other disease systems. This application proposes to test the efficacy of AIDS vaccine in morphine-dependent macaques. The proposed studies are highly warranted because there is no information available regarding effect of any vaccine in drug-addicted population. Therefore this study will provide guidelines not only in setting of future AIDS vaccine, but also provide guidelines regarding use of any vaccine in such high-risk population.